Sulphonyl compound

ABSTRACT

Compound of the formula I ##STR1## wherein the substituents have the meanings given in the description, are new active bronchodilators.

SCOPE OF APPLICATION OF THE INVENTION

The invention relates to new sulphonyl compounds, processes for theirpreparation, their use and medicaments containing them. The compoundsaccording to the invention are used in the pharmaceutical industry forthe preparation of medicaments.

KNOWN TECHNICAL BACKGROUND

Substituted benzo-naphthyridines which are distinguished by a pronouncedinhibition of blood platelet aggregation are described in DE-OS 21 23328 and in U.S. Pat. No. 3,899,494. The use of the compound with theproposed INN benafentrin, which falls under these protective rights, asa bronchodilator and for the treatment of inflammatory diseases of therespiratory tract is disclosed in European Patent Application 247 971.

DESCRIPTION OF THE INVENTION

It has now been found that the compounds described in more detail below,which differ from the compound benafentrin in particular by thesulphonyl substitution instead of the acetyl substitution on the aminogroup, have surprising and particularly advantageous properties.

The invention thus relates in a first aspect to compounds of the formulaI ##STR2## wherein R1 denotes 1-4C,-alkyl,

R2 denotes hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy,

R3 denotes hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy,

R4 denotes hydrogen (H), methyl or methoxy,

R5 denotes hydrogen (H) or 1-4C-alkyl and

R6 denotes 1-4C-alkyl, phenyl or substituted phenyl with one or twoidentical or different substituents from the group comprising1-4C-alkyl, 1-4C-alkoxy, hydroxyl and halogen,

and their salts.

1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1to 4 carbon atoms. Examples which may be mentioned are the butyl,iso-butyl, sec.-butyl, tert.-butyl, propyl, isopropyl, ethyl and inparticular the methyl radical.

1-4C-Alkoxy radicals contain one of the abovementioned 1-4C-alkylradicals in addition to the oxygen atom. The methoxy radical ispreferred.

Halogen in the context of the present invention is bromine, chlorine orfluorine.

Examples which may be mentioned of substituted phenyl radicals R6 arethe radicals: 4-methylphenyl, 4-tert.-butylphenyl, 4-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl and 4-hydroxyphenyl.

Preferred possible salts for compounds of the formula I are all the acidaddition salts. Salts which may be mentioned in particular are thepharmacologically tolerated salts of the inorganic and organic acidsusually used in galenics. Salts which are not pharmacologicallytolerated and may initially be obtained, for example, as processproducts during preparation of the compounds according to the inventionon an industrial scale are converted into pharmacologically toleratedsalts by processes which are known to the expert. Examples of suchsuitable salts are water-soluble and water-insoluble acid additionsalts, such as the hydrochloride, hydrobromide, hydriodide, phosphate,nitrate, sulphate, acetate, citrate, gluconate, benzoate, hibenzate,fendizoate, butyrate, sulphosalicylate, maleate, laurate, realate,fumarate, succinate, oxalate, tartrate, aresonata, embonate,metembonate, stearate, rosylate, 3-hydroxy-2-naphthoate or mesylate.

Compounds of the formula I which are to be singled out are those inwhich

R1 denotes 1-4C-alkyl,

R2 denotes 1-4C-alkoxy,

R3 denotes 1-4C-alkoxy,

R4 denotes hydrogen or methyl,

R5 denotes hydrogen or 1-4C-alkyl and

R6 denotes 1-4C-alkyl, phenyl or substituted phenyl with one substituentfrom the group comprising 1-4C-alkyl, 1-4C-alkoxy and halogen,

and their salts.

Compounds of the formula I which are to be singled out in particular arethose in which

R1 denotes methyl,

R2 denotes methoxy,

R3 denotes methoxy and

R4 denotes hydrogen or methyl, the radical -N(R5)SO₂ R6 is in the4-position of the phenyl radical bonded in the 6-position on thebenzo-naphthyridine ring,

R5 denotes hydrogen, methyl or ethyl and

R6 denotes methyl, 4-methylphenyl, 4-methoxyphenyl or 4-fluorophenyl,

and their salts.

The benzo-naphthyridine ring has (at positions 4a and 10b) two chiralitycenters. The invention therefore relates to all the conceivableenantiomers and diastereomers, as well as the racemates and mixturesthereof. Those compounds of the formula I in which the hydrogen atomspositions 4a and 10b are in the cis-position are preferred.

The enantiomerically pure cis-compounds which are mirror images of oneanother and rotate linearly polarized light in the (+) or (-) direction[(+)-enantiomer and (-)-enantiomer] are particularly preferred. Thetrans-compounds are separated from the (diastereomeric)cis-compounds--in the same way as the (+)- and (-)-enantiomers areseparated--in a manner with which the expert is familiar, e.g. asdescribed in European Patent Application 247 971.

Those compounds of the formula I which are derived from compounds of theformula II which have the same absolute configuration as the compound(-)-cis-6-(4-aminophenyl )-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methylbenzo[c][1,6]-naphthyridine with the opticalrotation of ##STR3## (c=1, chloroform), are particularly preferred inthis connection.

The invention furthermore relates to a process for the preparation ofthe compounds of the formula I according to the invention and theirsalts. process is characterized in that

a) compounds of the formula II ##STR4## wherein R1, R2, R3, R4 and R5have the abovementioned meanings, are reacted with sulphonyl compoundsof the formula III ##STR5## wherein R6 has the abovementioned meaningand X represents a suitable leaving group, or in that

b) to prepare compounds I in which R5 denotes 1-4C-alkyl, compounds ofthe formula I in which R5 denotes hydrogen are alkylated with analkylating agent of the formula IV

    Y--R5                                                      (IV)

wherein R5 denotes 1-4C-alkyl and Y denotes a leaving group, or in that

c) compounds of the formula V ##STR6## wherein R1, R2, R3, R4, R5 and R6have the abovementioned meanings, are subjected to a cyclocondensationreaction, and in that, if desired, the compounds I obtained according toa), b) or c) are then converted into their salts, or in that, ifdesired, the compounds I are then liberated from resulting salts of thecompounds I.

The reaction of the compounds II with the compounds III is carried outin inert solvents in a manner known to the expert for the preparation ofsulphonamides. The leaving group X is preferably a halogen atom, inparticular a chlorine atom. The reaction is preferably carried out inthe presence of an auxiliary base, e.g. an organic amine, such astriethylamine or pyridine, or e.g. a carbonate, such as potassiumcarbonate or sodium carbonate.

The N-alkylation according to process variant b) is carried out in amanner with which the expert is familiar, if appropriate under phasetransfer conditions, preferably in the presence of suitable bases orafter prior deprotonation of the compounds I where R5=hydrogen.

Possible deprotonating agents are, above all, those agents for which theacidity of the proton on the nitrogen is high enough to achieve anionformation. In addition to organometallic compounds, such as e.g.butyllithium, examples which may be mentioned are metal hydrides, inparticular sodium hydride, or alkali metal alcoholates, e.g. sodiummethylate or potassium tert.-butylate, or alkali metal hydroxides, e.g.sodium hydroxide or potassium hydroxide, or alkali metal carbonates,e.g. sodium carbonate.

The leaving group Y of the compounds IV is a group which is easily splitoff during the reaction of Y - R5 with the deprotonated I, for example ahalogen atom, such as chlorine, bromine or iodine, or the alkyl-sulphategroup.

The deprotonation and subsequent N-alkylation are carried out in inert,anhydrous solvents, such as are suitable for working with powerfuldeprotonating agents, or in water-solvent mixtures, such as are employedwhen working under phase transfer conditions. Examples which may bementioned are open-chain or cyclic ethers, such as diethyl ether,dioxane or tetrahydrofuran, or solvents, such as DMF or DMSO. Examplesof water/solvent mixtures which may be mentioned are mixtures of waterwith chloroform, methylene chloride or benzene. The reaction ispreferably carried out under mild reaction conditions at temperatures ofabout or below 0° C.

The cyclocondensation according to process variant c) is carried out inmanner which is known per se to the expert by the Bischler-Napieralskimethod in the presence of a suitable condensing agent, such as, forexample, polyphosphoric acid, phosphorus pentachloride, phosphoruspentoxide or preferably phosphorus oxytrichloride, in a suitable inertsolvent, e.g. in a chlorineted hydrocarbon, such as chloroform, or in acyclic hydrocarbon, such as toluene or xylene, or another inert solvent,such as acetonitrile, or without a further solvent using an excess ofcondensing agent, preferably at elevated temperature, in particular atthe boiling temperature of the solvent or condensing agent used.

The compounds of the formula II where R5=hydrogen are known from DE-OS21 23 328, U.S. Pat. No. 3,899,494 or EP-A-247 971, or they can beprepared in a manner analogous to that described in the abovespecifications. Compounds II where R5=1-4C-alkyl can be prepared fromthe compounds II where R5=hydrogen by alkylation in a manner with whichthe expert is familiar.

The compounds of the formula V are obtained in a manner which is knownper se from the compounds VI and VII according to the following equation##STR7## wherein R1, R2, R3, R4, R5 and R6 have the abovementionedmeanings and Y represents a leaving group, for example a chlorine atom.

The compounds VI are known e.g. from DE-OS 21 23 328 or EP-A-247 971, orthey can be prepared in an analogous manner. The compounds VII arelikewise known, or can be prepared in a manner which is known to theexpert.

To prepare enantiomerically pure compounds I, the separation of thetrans-compounds from the cis-compounds as well as the separation of the(+)- and (-)-enantiomers is carried out preferably on the step of thecompounds II which are known from EP-A-247 971 or which can be preparedand separated as described there.

The following examples illustrate the invention in more detail, withoutlimiting it. The invention preferably relates to the compounds of thegeneral formula I listed by name in the examples and the salts of thesecompounds. M.p. denotes melting point, and the abbreviation h is usedfor hour(s) and the abbreviation min for minutes. Decomp. representsdecomposition. "Ether" is understood as meaning diethyl ether.

EXAMPLES 1.rac-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-(4-methylsulphonamidophenyl)-benzo[c][1,6]naphthyridine

A solution of 0.6 ml methanesulphonyl chloride in 3 ml absolute dioxaneis added dropwise to a solution of 2.1 grac-cis-6-(4-aminophenyl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-benzo[c ][1,6]naphthyridine in 20 ml absolutepyridine, and the mixture is then stirred at 60° C. for a further 3 h.After cooling, the mixture is poured onto 100 ml of an ice/watermixture, rendered alkaline with dilute sodium hydroxide solution andextracted with n-butanol. After the n-butanol has been evaporated off,the residue which remains is extracted with methylene chloride and theorganic phase is dried over sodium sulphate and then concentrated. 2.4 gof the title compound are obtained as the residue and are converted intothe dihydrochloride with ethereal HCl, and the product is recrystallizedfrom non-dried methanol. Yield: 2.3 g of the title compound as thedihydrochloride hydrate. M.p. 239°-240° C. (decomposition).

2.rac-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-toluenesulphonamido)-phenyl]-benzo[c][1,6]naphthyridine

The title compound is obtained analogously to Example 1 ifp-toluenesulphonyl chloride is employed instead of methanesulphonylchloride. M.p. 219°-221° C. (dihydrochloride hydrate).

3.rac-cis-8.9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-methyl-3-(p-toluenesulphonamido)-phenyl]-benzo[c][1,6]naphthyridine

3.9 grac-cis-3-(3,4-dimethoxyphenyl)-1-methyl-4-[4-methyl-3-(p-toluene-sulphonamido)-benzamido]-piperidineare heated at the boiling point under reflux in 50 ml phosphorusoxytrichloride for 3 h. After the excess phosphorus oxytrichloride hasbeen distilled off, the residue is partitioned between methylenechloride and 2 N sodium hydroxide solution, and the organic phase iswashed with water and dried over sodium sulphate. After the methylenechloride has been distilled off, the residue is purified by silica gelchromatography. The main product fraction which has been separated offis concentrated and the solid residue is recrystallized from ethylacetate/petroleum ether. 2.6 g of the title compound are obtained asyellowish crystals of m.p. 206°-210° C. (decomp.).

The starting compoundrac-cis-3-(3,4-dimethoxyphenyl)-l-methyl-4-[4-methyl-3-(p-toluenesulphonamido)-benzamido]-piperidineis obtained by reaction of 4.6 g4-methyl-3-(p-toluenesulphonamido)-benzoyl chloride with 3.0 grac-cis-4-amino-3-(3,4-dimethoxyphenyl)-1-methylpiperidine and 4 mltriethylamine in 50 ml anhydrous methylene chloride. After extraction byshaking with NaHCO₃ solution, drying of the organic phase over sodiumsulphate and concentration, the residue is recrystallized from methanol.Yield: 4.2 g, m.p. 142°-146° C.

4.rac-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[2-(p-toluenesulphonamido)-phenyl]-benzo[c][1,6]naphthyridine

The title compound is obtained analogously to Example 3 from 4.5 grac-cis-3-(3,4-dimethoxyphenyl )-1-methyl-4-[2-(p-toluenesulphonamido)-benzamido]-piperidine and 30 ml phosphorus oxytrichloride. Yield: 3-3g brownish crystals.

The starting compoundrac-cis-3-(3,4-dimethoxyphenyl)-1-methyl-4-[2-(p-toluenesulphonamido)-benzamido]-piperidineis obtained analogously to Example 3 from2-(p-toluenesulphonamido)-benzoyl chloride and the correspondingpiperidine. Yield: 70%.

5.rac-cis-8.9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-methoxyphenylsulphonamido)-phenyl]-benzo[c][1,6]naphthyridine

The title compound is obtained analogously to Example 1 ifp-methoxyphenylsulphonyl chloride is employed. Yield: 66%, m.p.210°-217° C. (as the carbonate hydrate crystallized from methanol).

Alternatively, the title compound is obtained analogously to Example 3ifrac-cis-3-(3,4-dimethoxyphenyl)-1-methyl-4-[(4-p-methoxyphenylsulphonamido)-benzamido]-piperidineis subjected to cyclocondensation. The starting compound is obtainedanalogously to Example 3 if 4-(p-methoxyphenylsulphonamido)-benzoylchloride is employed.

6.rac-cis-8.9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-fluorophenylsulphonamido)-phenyl]-benzo[c][1,6]naphthyridine

The title compound is obtained analogously to Example 3 fromrac-cis-3-(3,4-dimethox yphenyl)-1-methyl-4-[(p-fluorophenylsulphonamido) -benzamido]-piperidine.Yield: 69%, m.p. 163°-165° C.

The starting compound is obtainable analogously to Example 3 from4-(p-fluorophenylsulphonamido)-benzoyl chloride. Yield: 60%, m.p.108°-113° C.

7.rac-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-toluenesulphon-N-methylamido)-phenyl]-benzo[c][1,6]naphthyridine

The title compound is obtained analogously to Example 3 fromrac-cis-3-(3,4-dimethoxyphenyl)-1-methyl-4-[(p-toluenesulphon-N-methylamido)benzamido]-piperidine;yield: 53%, m.p. 157°-158° C. (from methanol/ether).

The starting compound is obtainable analogously to Example 3 from4-(p-toluenesulphon-N-methylamido)-benzoyl chloride.

8.rac-cis-8.9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-toluenesulphon-N-ethylamido)-phenyl]-benzo[c][1,6]naphthyridine

The title compound is obtained analogously to the above example ifinstead of the N-methyl compounds the corresponding N-ethyl compoundsare employed. Yield: 71%, m.p. 160°-166° C. (carbonate).

9.(-)-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-toluenesulphonamido)-phenyl]-benzo[c][1,6]naphthyridine

The title compound is obtained analogously to Example 1 if(-)-cis-6-(4-aminophenyl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-benzo[c][1,6]naphthyridine##EQU1## (c=1, CHCl₃) is reacted with p-toluenesulphonyl chloride. Yield82%, m.p. 178°-183° C. (yellowish crystals from ethyl acetate/methanol);##EQU2## (in each case c=1, methanol).

10.(+)-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-toluenesulphonamido)-phenyl]-benzo[c][1,6]naphthyridine

The title compound is obtained analogously to Example 9 if(+)-cis-6-(4-aminophenyl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-benzo[c][1,6]naphthyridine##EQU3## (c=1, CHCl₃) is employed. Yield: 81%, m.p. 180°-181° C.(yellowish crystals from ethyl acetate/methanol); ##EQU4## (c=1,methanol).

The starting compounds (+)-cis-and(-)-cis-6-(4-aminophenyl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-benzo[c][1,6]naphthyridineare known from EP-A-247 971.

COMMERCIAL USEFULNESS

The sulphonyl compounds according to the invention have pharmacologicalproperties which render them commercially usable. They are distinguishedabove all by those properties which reveal them as being suitable forthe therapy of diseases of the respiratory tract of various origins. Inparticular, inflammatory and allergen-induced bronchial diseases can betreated on the basis of the antiinflammatory and broncholytic activityof the compounds according to the invention. The compounds according tothe invention are distinguished here by a very low toxicity, a widetherapeutic range, a long-lasting action and the absence of substantialside effects. The sulphonyl compound according to the inventionadditionally have antihypertensive properties.

The broncholytic and antiinflammatory activity of the sulphonylcompounds according to the invention enable them to be used in human andveterinary medicine, in which they are used for the treatment andprophylaxis of illnesses based on diseases of the bronchi. For example,acute and chronically obstructive diseases of the respiratory tract ofvarious origins (bronchitis, allergic bronchitis, bronchial asthma) inhumans and animals can be treated. On the basis of the antihypertensiveactivity, the compounds according to the invention can also be used forthe treatment of hypertensive diseases of various origins and theassociated concomitant diseases.

The invention thus furthermore relates to a method for the treatment ofmammals, including humans, suffering from one of the abovementionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically tolerated amount of one or more of the compoundsaccording to the invention is administered to the sick mammal.

The invention furthermore relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of the illnessesmentioned.

The invention likewise relates to the use of the compounds according tothe invention for the preparation of medicaments which are employed forthe treatment and/or prophylaxis of the illnesses mentioned.

The invention furthermore relates to medicaments for the treatmentand/or prophylaxis of the illnesses mentioned, which contain one or moreof the compounds according to the invention and/or theirpharmacologically tolerated salts.

The medicaments according to the invention are prepared by processeswhich are known per se, reference being made, for example, to thestatements in European Patent 163 965 with regard to formulations,dosages, and presentation forms. Inhalative administration, for whichthe compounds according to the invention appear to be outstandinglysuitable on the basis of their action profile, is of particularimportance in the treatment of bronchial diseases in this connection.

PHARMACOLOGY

The bronchospasmolytic action of the compounds according to theinvention can be demonstrated on various in vitro and in vivo models. Inthe following table, the substances analyzed have been given numberswhich correspond to the numbers of the substances in the examples.

BRONCHOSPASMOLYTIC ACTION AFTER I.T. INSTILLATION ON THE MODEL OF THEANAESTHETIZED GUINEA PIG

The compounds according to the invention were investigated in moredetail for their bronchospasmolytic action after i.t. instillation onthe model of the anesthetized guinea pig as follows:

Animals

Male guinea pigs, Dunkin-Hartley, Charles-River/Wiga, weight 300-450 g,N=6 animals per test group.

Method

Urethane anaesthesia; preparation of the v. jugularis for i.v. histamineadministration; introduction of a Y-shaped tracheal catheter formeasurement of the flow and for i.t. administration of the testsubstance; introduction of a blunt, short pleural catheter formeasurement of the pleural pressure; determination of the lung functionparameters of compliance and conductance (=1/resistance) by means of aBuxco lung function analyser; PC-assisted recording of the measurementdata.

Triggering off of histamine-induced bronchospasms 20 and 10 min beforeand 2, 10, 30 and 60 min after administration of the substance; for thecompliance and conductance, the baseline values before each bronchospasmand the delta-% changes during the bronchospasm are recorded by means ofthe PC program (T=4 sec); these data form the basis of the laterevaluation.

Provocation solution: histamine 4 or 5 μg/kg (=22 or 27 nmol/kg) i.v.dissolved in 0.9% NaCl solution, administration volume 1 ml/kg, bolusinjection; inclusion criterion: compliance decrease 70-90%. The testsubstances are ground in the wet state, if they are not water-soluble,and are administered in a dose of 3 μmol/kg in an application volume of0.1 ml/kg i.t. 1% Tween 80 is added to the ready-to-administersuspension. A substance-free 10% succinyl-gelatine/aqua dist. solutioncontaining 1% Tween 80 is used as the placebo solution by the same modeof administration and in the same administration volume.

Result

The percentage inhibition of the histamine-induced bronchoconstrictionafter i.t. administration of 3 μmol/kg substance in comparison with theplacebo group is shown in the following Table 1. The average percentagebronchospasmolytic action over 60 min (act. 0-60), the maximumpercentage bronchospasmolytic action (act. max) and the percentagebronchospasmolytic action at the time 60 min post appl. (act. 60) ineach case in comparison with the corresponding placebo, have beencalculated.

    ______________________________________                                               Conductance  Compliance                                                Substance                                                                              act.   act.     act. act.   act. act.                                no.      0-60   max      60   0-60   max  60                                  ______________________________________                                        1        55%    61%      51%  34%    37%  35%                                 2        61%    84%      60%  47%    72%  40%                                 9        57%    71%      51%  56%    70%  45%                                 ______________________________________                                    

We claim:
 1. A compound of formula I ##STR8## wherein R1 denotes1-4C-alkyl,R2 denotes hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy, R3denotes hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy, R4 denotes hydrogen(H), methyl or methoxy, R5 denotes hydrogen (H) or 1-4C-alkyl and R6denotes 1-4C-alkyl, phenyl or substituted phenyl with one or twoidentical or different substituents selected from the group consistingof 1-4C-alkyl, 1-4C-alkoxy, hydroxyl and halogen,or a salt thereof.
 2. Acompound of the formula I according to claim 1, in whichR1 denotes1-4C-alkyl, R2 denotes 1-4C-alkoxy, R3 denotes 1-4C-alkoxy, R4 denoteshydrogen or methyl, R5 denotes hydrogen or 1-4C-alkyl and R6 denotes1-4C-alkyl, phenyl or substituted phenyl with one substituent selectedfrom the group consisting of 1-4C-alkyl, 1-4C-alkoxy and halogen,or asalt thereof.
 3. A compound of formula I according to claim 1, inwhichR1 denotes methyl, R2 denotes methoxy, R3 denotes methoxy and R4denotes hydrogen or methyl, the radical -N(R5)SO₂ R6 is in the4-position of the phenyl radical bonded in the 6-position on thebenzo-naphthyridine ring, R5 denotes hydrogen, methyl or ethyl and R6denotes methyl, 4-methylphenyl, 4-methoxyphenyl or 4-fluorophenyl,or asalt thereof.
 4. A compound of claim: which israc-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-6-(4-methylsulphonamidophenyl)-2-methylbenzo[c][1,6]naphthyridine,or a salt thereof.
 5. A compound of claim 1: which israc-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-toluenesulphonamido)-phenyl]-benzo[c][1,6]naphthyridine,or a salt thereof.
 6. A compound of claim 1: which is(-)-cis-8,9-Dimethoxy-1,2,3,4,4a,10b-hexahydro-2-methyl-6-[4-(p-toluenesulphonamido)-phenyl]-benzo[c][1,6]naphthyridine,or a salt thereof.
 7. A pharmaceutical composition comprising aneffective amount of a compound of claim 1 and/or of a pharmacologicallytolerated salt thereof, and pharmaceutically acceptable diluent orcarrier therefor.
 8. In a process for treating a disease of the bronchiwhich comprises administering an effective amount of an activeingredient to a mammal afflicted with said disease, the improvementwherein the active ingredient is a compound of claim 1 or apharmacologically-tolerated salt thereof.
 9. In a method of compoundinga pharmaceutical composition comprising an active ingredient for thetreatment of a disease of the bronchi, the improvement comprisingincorporating in the composition a compound of claim 1, or apharmacologically-tolerated salt thereof, as the active ingredient.